Predictors of Immunologic Failure in Older Adults

老年人免疫失败的预测因素

• 批准号: 7797075
• 负责人: DAVID H CANADAY
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7797075
• 关键词: Accounting; Address; Adult; Age; Aged, 80 and over; Aging; Algorithms; Antibodies; Antibody Formation; Antigen-Presenting Cells; B-Lymphocytes; Biological Markers; Body Weight decreased; Categories; Cessation of life; Clinical; Clinical Trials; Communities; Comorbidity; Country; Data Set; Defect; Elderly; Enrollment; Europe; Failure; Functional disorder; Geriatrics; Immune; Immune System Diseases; Immune system; Immunologic Tests; Immunologics; Incidence; Individual; Infection; Influenza; Influenza vaccination; Long-Term Care; Measures; Mediating; Modeling; Morbidity - disease rate; Mortality Decline; Patients; Performance; Phenotype; Pneumonia; Population; Prevalence; Prophylactic treatment; Research Personnel; Risk; Schedule; Speed; Syndrome; System; T-Lymphocyte; Testing; Vaccinated; Vaccination; Vaccines; Validation; Veterans; Walking; age group; aged; base; disability; exhaustion; frailty; immune function; indexing; influenza outbreak; influenza virus vaccine; instrument; mortality; novel vaccines; protective efficacy; public health relevance; response; stressor; success; tool

DESCRIPTION (provided by applicant): Historically the term frailty has been interchanged with co-morbidity, disability, and extreme old age. In the last decade Geriatrics researchers have developed, refined, and validated a concept of frailty. It is a syndrome that at its core involves a clinical state of vulnerability to stressors thought to be due to "multisystem dysregulation". The criteria of measuring a Frailty Index include: unintentional weight loss, exhaustion, loss of strength, slow walking speed, and low level of activity. The Frailty Index is a validated instrument that classifies older adults into three defined categories: robust (healthy), pre-frail, and frail. There is a clear association between frailty, increased mortality, and declines in other performance measures in several ethnic populations in the U.S. and Europe. Frailty is a common condition in community dwelling elderly adults with a prevalence 7-10 % among those age 65, 25% in individuals over age 80, and even higher in individuals in long-term care facilities. Pre-frailty is an intermediate category between robust and frail, and predicts progress to frailty. The incidence of pre-frailty is even more common than frailty. The current level of understanding of the immune system in older individuals is based almost exclusively on age. There have been very few immunologic studies that have addressed any relationship between immunologic dysfunction and frailty. Older individuals, especially ones with greater debility and frailty, are largely excluded from clinical trials and are significantly understudied. It has been established that increasing age leads to both immunologic dysfunction and poor responses to vaccination. The overall hypothesis that frailty and age predict immunologic and vaccination failure in older adults. However, frailty will be a stronger predictor than age of immunologic and vaccination failure. This hypothesis will be addressed with the following specific Aims: Aim 1. To determine the relationship between frailty and immunologic dysfunction in older adults. The hypothesis is that certain immune defects will be more strongly associated with frailty than age. To test this hypothesis, a panel of established immunologic tests to measure the function of T cells, antigen presenting cells (APC), and B cells in older adults that are robust (healthy), pre-frail, and frail as measured by a Frailty Index will be used. Subjects will be enrolled in the age groups of 65-74, 75-84 and over 85 years to allow a direct comparison of specific aspects of immunologic function between frailty and age. The studies in the immunologic panel will focus on T cell, APC, and B cell phenotypes and functions that are critical for a successful vaccine response. We predict that the T cell compartment will demonstrate the greatest dysfunction with advancing frailty and age. Aim 2. To determine the relationship between frailty status and poor influenza vaccine response in older adults. We hypothesize that vaccine failure correlates closely with frailty as well as age. To test this hypothesis, we will vaccinate the same frailty and age matched subjects in Aim 1 with trivalent inactivated influenza vaccine and measure antibody responses after 4-12 weeks. Aim 3. To determine which specific immunologic dysfunction(s) mediate the relationship between frailty and poor influenza vaccine responses. The specific immune defects observed (Aim 1) that mediate the reduced influenza-specific antibody titers that result from vaccination (Aim 2) will be determined in the frailty groups with age as a covariable. Taking into account the influence of frailty and age, we will determine which immune functions most likely are the mechanism(s) of the poor vaccine response. Aim 4. To develop a clinical algorithm to predict the efficacy of influenza vaccination based on categories of frailty and age. We will use the 3 frailty categories and 3 age groups to develop a clinically useful algorithm to predict influenza vaccine success and failure. This tool could guide use of prophylaxis and alternative protective strategies clinically. PUBLIC HEALTH RELEVANCE: The proposed studies are highly significant to the Veteran population. Over 9 million veterans comprising of 39% of patients in the VA system are 65 or older. Around 90% of influenza-related deaths occurred among adults aged >65 years in the United Sates. The risk of mortality due to influenza is increased in older individuals in spite of an aggressive vaccination campaign. Identification and validation of specific biomarkers of protective vaccination in older adults with and without frailty and the algorithm of estimation of protective efficacy could help determine who might require additional protective measures in the setting of an influenza outbreak. New vaccines and/or administration schedules need to be developed to tailor to the needs of the aging immune system. In order to achieve this, it is necessary to have an increased understanding of the immune dysfunction in older veterans to identify what specific defects must be overcome.

描述（由申请人提供）： 从历史上看，“虚弱”一词一直与共病、残疾和高龄互换。在过去的十年中，老年病学研究人员开发、完善并验证了虚弱的概念。这是一种综合症，其核心涉及一种易受压力源影响的临床状态，被认为是由于“多系统失调”所致。衡量虚弱指数的标准包括：无意识的体重减轻、疲惫、力量丧失、步行速度缓慢和活动量低。虚弱指数是一种经过验证的工具，它将老年人分为三个明确的类别：健壮（健康）、虚弱前和虚弱。在美国和欧洲的一些种族人群中，虚弱、死亡率增加和其他表现指标下降之间存在明显的关联。衰弱是社区居住老年人的常见状况，65 岁老年人的患病率为 7-10%，80 岁以上老年人的患病率为 25%，长期护理机构的老年人患病率甚至更高。虚弱前期是介于健壮和虚弱之间的中间类别，预示着虚弱的进展。衰弱前的发生率甚至比衰弱期更常见。 目前对老年人免疫系统的了解水平几乎完全基于年龄。很少有免疫学研究探讨免疫功能障碍和虚弱之间的关系。老年人，尤其是体质较弱的老年人，很大程度上被排除在临床试验之外，而且研究也明显不足。 已经确定，年龄的增长会导致免疫功能障碍和疫苗接种反应不佳。总体假设是，虚弱和年龄可预测老年人的免疫和疫苗接种失败。然而，虚弱将是比年龄更强的免疫和疫苗接种失败预测因素。这一假设将通过以下具体目标来解决： 目标 1. 确定老年人虚弱与免疫功能障碍之间的关系。假设认为，某些免疫缺陷与虚弱的关系比年龄更密切。为了检验这一假设，我们建立了一组免疫学测试来测量老年人中 T 细胞、抗原呈递细胞 (APC) 和 B 细胞的功能，这些老年人中的强健（健康）、脆弱前和脆弱（通过脆弱性测量）将使用索引。受试者将被纳入 65-74 岁、75-84 岁和 85 岁以上年龄组，以便直接比较虚弱和年龄之间免疫功能的特定方面。免疫学小组的研究将重点关注对成功的疫苗反应至关重要的 T 细胞、APC 和 B 细胞表型和功能。我们预测，随着身体虚弱和年龄的增长，T 细胞区室将表现出最大的功能障碍。目标 2. 确定老年人虚弱状况与流感疫苗反应不佳之间的关系。我们假设疫苗失败与虚弱和年龄密切相关。为了检验这一假设，我们将给目标 1 中相同的虚弱且年龄匹配的受试者接种三价灭活流感疫苗，并在 4-12 周后测量抗体反应。目标 3. 确定哪些特定的免疫功能障碍介导了虚弱与流感疫苗反应不良之间的关系。观察到的特异性免疫缺陷（目标 1）介导了疫苗接种导致的流感特异性抗体滴度降低（目标 2），将在虚弱组中以年龄作为协变量来确定。考虑到虚弱和年龄的影响，我们将确定哪些免疫功能最有可能是疫苗反应不佳的机制。目标 4. 开发一种临床算法，根据虚弱和年龄类别预测流感疫苗接种的效果。我们将使用 3 个虚弱类别和 3 个年龄组来开发一种临床上有用的算法来预测流感疫苗的成功和失败。该工具可以指导临床上预防和替代保护策略的使用。 公共卫生相关性： 拟议的研究对退伍军人群体非常重要。 VA 系统中有超过 900 万退伍军人，其中 39% 的患者年龄在 65 岁或以上。在美国，大约 90% 的流感相关死亡发生在 65 岁以上的成年人中。尽管开展了积极的疫苗接种活动，但老年人因流感死亡的风险仍然增加。识别和验证有或没有虚弱的老年人的保护性疫苗接种的特定生物标志物以及保护效果的估计算法可以帮助确定在流感爆发的情况下谁可能需要额外的保护措施。需要开发新的疫苗和/或给药方案以满足衰老免疫系统的需求。为了实现这一目标，有必要加深对老年退伍军人免疫功能障碍的了解，以确定必须克服哪些具体缺陷。